Oral Estradiol Valerate Research Articles

The effect of hormone replacement therapy on the oxidation of low density lipoprotein in postmenopausal women

The oxidative modification of low density lipoprotein (LDL) is important in the pathogenesis of atherosclerosis, and oestrogen has been shown to inhibit copper and cell mediated oxidation of LDL in vitro. We have investigated the effect of oral and transdermal oestrogens (oestradiol valerate 1 mg, conjugated equine oestrogens 0.625 mg and patches releasing 50 μg oestradiol daily), oestrogen implants (oestradiol 50 mg) and oral combined oestrogen and progestogen (oestradiol valerate 2 mg with medroxyprogesterone acetate 5 mg and oestradiol valerate 2 mg with norethisterone acetate 1 mg), on the susceptibility of LDL to oxidation in postmenopausal women (total n=56). Oxidation of LDL was initiated by the addition of copper ions, and monitored by measurement of conjugated dienes. Changes in fasting serum levels of total cholesterol, LDL, HDL and triglycerides were also evaluated, as were changes in LDL composition. Total cholesterol decreased by 5.5% ( P<0.05) with CEE, 6.8% with oestradiol implants ( P<0.05), 9.3% with oestradiol+MPA ( P<0.01) and 10% with oestradiol+norethisterone ( P<0.05). There were reductions in LDL with oral oestradiol valerate (7.8%) ( P<0.05), CEE (13.8%) ( P<0.01) and oestradiol combined with MPA (12.7%) ( P<0.05). HDL increased by 7.1% ( P<0.01) and 6.3% ( P<0.05), with oestradiol valerate and CEE respectively, and decreased by 9% ( P<0.05) with implants and by 14.7% with oestradiol combined with norethisterone ( P<0.01). Triglycerides were significantly increased with CEE (14.9%) and reduced with oestradiol implants (15.2%) (both P<0.05). While there was no change in the ratio of `cholesterol ester' to `free cholesterol' within LDL with any of the HRT preparations, a reduction in total cholesterol and cholesterol ester content of LDL occurred with transdermal oestradiol and a reduction in free cholesterol occurred with oestradiol plus MPA. Although we found a small but significant decrease in plasma hydroperoxide concentration four weeks after insertion of the oestradiol implant from 1.17±0.06 to 1.03±0.04 μmol/l ( P<0.05), we found no significant change in the lag time to oxidation, or in the maximum rate of propagation of the reaction, after treatment with any of the above forms of hormone replacement therapy. This study does not therefore support the role of oestrogens as antioxidants in vivo.

Oocyte donation in Turner's syndrome: an analysis of the factors affecting the outcome.

A total of 29 women with Turner's syndrome (19 monosomy and 10 mosaic) had 68 cycles of oocyte donation that included 29 cycles of initial attempt and 39 cycles of subsequent attempts. Oral oestradiol valerate was used either in a variable dose (42 cycles) or in a constant dose (26 cycles) regimen for the endometrial preparation which was monitored by pelvic ultrasonography. The embryos/zygotes were transferred either fresh (50 cycles) or after cryopreservation (18 cycles) into the Fallopian tube (41 cycles) and uterine cavity (27 cycles) as appropriate. There were 28 clinical pregnancies including two sets of triplets resulting in a pregnancy rate of 41.2% per treatment cycle and an implantation rate of 17.1% per embryo transferred. The recipient's age, chromosomal constitution or associated uterine or tubal anomaly had no influence on the treatment outcome. The implantation and pregnancy rates were higher in the subsequent than initial cycles (22.6 versus 9.99%, P < 0.05; 51.3 versus 27.6%, P < 0.05). An endometrial thickness of > or = 6.5 mm was an important predictor of pregnancy but the endometrial echo pattern failed to predict the outcome. Although the total dose of oestradiol before embryo transfer was higher in the pregnant cycles than the non-pregnant ones and its gradation (< 50 mg, 50-100 mg, < 100 mg) influenced the implantation (3.4, 17.5, 26.3% respectively, P < 0.05) and pregnancy rates (10, 42.2, 61.5% respectively, P < 0.05), the effect was indirect by altering the endometrial thickness. The number of oocytes fertilized affected the pregnancy rate irrespective of the number of embryos transferred. The implantation and pregnancy rates were higher when fresh rather than frozen-thawed embryos were transferred (20.3 versus 8.2%, P < 0.05; 48 versus 22.2%, P < 0.05) but the route of transfer was of no statistical importance. The overall miscarriage rate was higher (50%), and was related to the presence of hypoplastic or bicornuate uterus and to a low oocyte fertilization rate.

Further data favoring the hypothesis of the uterine first-pass effect of vaginally administered micronized progesterone.

Ten infertile women, 28 to 36 years of age, with regular menstrual cycles were treated with oral estradiol valerate and intravaginally administered micronized progesterone under pituitary suppression with leuprolide acetate. Patients underwent endometrial biopsies on cycle days 17 and 28 (luteal phase days 3 and 14) and blood sampling for plasma progesterone and estradiol determinations on cycle days 17, 21 and 26 (luteal phase days 3, 7 and 12). All ten endometrial biopsies on cycle day 17 were in-phase and only two out of ten (20%) were out-of-phase on cycle day 28. This produced an incidence of endometrial luteal phase deficiency that was not different from the 14% found among an infertile general population of 300 women. Midluteal estradiol plasma levels in the study group were similar to those found in a control group of fertile women, but progesterone levels were significantly lower on cycle day 21 in the treatment group. As much as 75% (six out of eight patients) of treated women having in-phase late luteal endometrial biopsies had low midluteal plasma progesterone levels, a situation that is found in only 3% of infertile patients (9/300) or 3.5% (9/258) of those infertile women with normal endometria (p = 0.03). Thus, the present study adds further evidence favoring the current postulate that vaginal micronized progesterone enhances hormone delivery to the uterus and this explains the marked discrepancy between the strong uterine effect and the relatively low plasma progesterone levels.

A reappraisal of the feedback effects of oestradiol upon luteinizing hormone surge.

The objective of this study was to assess the temporal relationships of serum oestradiol and luteinizing hormone (LH) with regard to the feedback mechanism leading to the LH surge. Daily measurements of oestradiol, LH and follicle stimulating hormone were made in 65 women with ovarian failure undergoing an evaluation of endometrial response to oral cycle stimulation. Patients received incremental oral oestradiol valerate for varying durations at the in-vitro fertilization unit of the Sheba Medical Center, Tel Hashomer, Israel. The treatment protocol involved the administration of daily oestradiol valerate, starting with 1 mg/day, followed by a daily increment of 1 mg for a total of 4, 6 and 8 days. After the last day, a daily maintenance dose of 2 mg was continued. Serum oestradiol concentrations correlated with the dose of oral oestradiol valerate. Peak oestradiol concentrations (mean +/- SEM) were 572 +/- 60, 721 +/- 42 and 797 +/- 53 pg/ml for 4, 6 and 8 days of oestradiol valerate administration respectively. Serum LH, after an initial suppression, peaked 2 days after maximal oestradiol valerate dose and 1 day after peak serum oestradiol. The magnitude of the LH peak was proportional to the duration of incremental oestradiol valerate treatment. In conclusion, the LH surge is temporally related to the cessation of serum oestradiol increase. Consequently, the occurrence of this surge can be explained by a simple negative feedback inhibition of pituitary LH release rather than by a dual negative/positive mechanism.

Pregnancy rate in an oocyte donation program.

Oocyte donation programs offer an alternative treatment for infertile women with ovarian failure or abnormal ovarian function. Seventeen cycles of in vitro fertilization and embryo transfer with donated oocytes were performed in 13 women, with a mean age of 34.8 years. The hormonal replacement therapy consisted of a fixed dose of oral estradiol valerate, 6 mg daily, and intramuscular progesterone in oil, 100 mg daily. Estrogen and progesterone were continued for 10 more weeks after embryo transfer if pregnancy was established. After 13 embryo transfers, 8 pregnancies were obtained, for a pregnancy rate per transfer of 61.5%. Today seven pregnancies are progressing normally, including one set of twins. This results suggest that an oocyte donation program using a fixed and simple hormonal replacement therapy is an adequate treatment for these infertile couples.

Replacement of frozen - thawed embryos in artificial and natural cycles: A prospective semi-randomized study

This prospective partly-randomized study assessed the relative efficacy of two strategies of patient management for the replacement of frozen-thawed embryos. A luteinizing hormone-releasing hormone (LHRH) agonist was used to induce a temporary hypogonadism in a group of patients who were then prepared for implantation by endometrial priming with hormone replacement therapy (HRT): oral oestradiol valerate and then oestradiol valerate and injections of progesterone. A second group of patients had their frozen-thawed embryos replaced during their natural cycles. Of the 84 patients treated with the LHRH regimen, 80 had embryos replaced and 16 (20%) clinical pregnancies were established. Of the 78 patients treated with natural cycles, 70 had embryos replaced and 14 (20%) achieved clinical pregnancies. There were no statistical differences between the two groups in terms of age, obstetric history, duration of infertility, number of oocytes retrieved and fertilized or the number of embryos frozen following ovarian stimulation in the embryo 'generating' cycle. In terms of pregnancy rates, both protocols were equally effective. However, the LHRH-HRT protocol was of great value in the management of oligomenorrhoeic patients and in establishing standard conditions for implantation in cyclic patients.

Serum-free gamma carboxyglutamic acid (free Gla) is a poor biochemical marker of bone resorption in early postmenopausal women

In this study, we assessed the potential value of serum-free Gla to reflect changes of bone turnover at menopause. Serum-free Gla was measured in 49 healthy postmenopausal women and 19 healthy age-matched premenopausal women. No difference in serum-free Gla concentrations was observed between the two groups. In a double-blind longitudinal study of 36 postmenopausal women (a subgroup of the above 49 women) treated with either oral oestradiol valerate in a cyclical combination with cyproterone actate ( n = 19) or placebo ( n = 17) for nine months, the serum-free Gla concentration was unchanged with placebo and decreased by only 10% after hormonal replacement therapy. Initial serum-free Gla concentrations in postmenopausal women did not correlate with other biochemical markers of bone turnover. The predictive value of serum-free Gla concentration for the spontaneous rate of bone loss in early postmenopause was also assessed, and the marker showed no correlation to bone loss. These data indicate that the serum concentration of free Gla is not a useful marker of the bone turnover rate in the early postmenopause.

Different implantation rates after transfers of cryopreserved embryos originating from donated oocytes or from regular in vitro fertilization

Most oocyte donation programs have experienced higher pregnancy rates than usually seen in regular in vitro fertilization (IVF), suggesting that the quality of either the oocytes or the endometrium is superior. To clarify this issue we analyzed the results of transfers of 136 cryopreserved embryos originating either from donated oocytes (18 transfers) or from regular IVF (118 transfers). Transfers of embryos originating from donated oocytes took place after administrating oral estradiol (E2) valerate and vaginal micronized progesterone (P) following a regimen designed to mimic the serum levels of E2 and P observed during the menstrual cycle. Transfers of embryos originating from regular IVF took place either in the natural cycle (53 transfers) or after suppressing ovarian function with a single injection of a gonadotropin-releasing hormone agonist (GnRH-a), Decapeptyl-Retard 3.75 mg, and administering the same hormone replacement regimen (E2/P) used in oocyte donation (65 transfers). Eighteen transfers involving 24 embryos originating from donated oocytes were affected, resulting in six pregnancies (4 ongoing). The ongoing pregnancy rate per transfer was 22%. Seventy-nine embryos originating from regular IVF were transferred (53 transfers) in the natural cycle resulting in six pregnancies (2 ongoing). One hundred three other embryos originating from regular IVF were transferred (65 transfers) after administration of GnRH-a and E2/P resulting in four pregnancies. The pregnancy rate after transfers of embryos originating from regular IVF was 9% per transfer. This was significantly less than the pregnancy rate of 33% per transfer seen after the transfers of embryos originating from donated oocytes. Our results indicated that a difference in embryo implantation persisted between oocyte donation and regular IVF even in the absence of ovarian hyperstimulation. This suggests, therefore, that either the embryos originating from donated oocytes are of higher quality than those originating from regular IVF, or that the endometrium is less receptive in IVF patients.

Plasma BGP: an indicator of spontaneous bone loss and of the effect of oestrogen treatment in postmenopausal women

One hundred and ninety-one healthy early postmenopausal women, aged 45-54 years, were randomized to 2 years of treatment with (a) percutaneous 17 beta-oestradiol combined with progesterone (n = 29) or placebo (n = 28); (b) oral oestradiol valerate combined with cyproterone acetate (n = 37) or placebo (n = 39); (c) 24R, 25 (OH)2D3 (n = 29) or placebo (n = 29). We measured the plasma bone Gla-protein (BGP), bone mineral content of the proximal forearms (BMC), bone mineral density in the spine (BMDspine) and total body bone mineral (TBBM) in all the women before, and during, the study. In the groups of women receiving the oestrogen preparations, the plasma BGP decreased highly significantly (P less than 0.001) to a premenopausal level. The initial plasma BGP concentration was significantly related to the loss of BMC (P less than 0.001) in the placebo groups. The changes in plasma BGP were an indicator of the oestrogen response on BMC. We conclude that serial determinations of plasma BGP are useful for determination of the effect of oestrogen therapy in groups of patients, and that plasma BGP measured at the time of the menopause indicates what the rate of bone loss will be.

Effect on plasma gonadotropins of cyclic steroid replacement in women with premature ovarian failure.

A sequential regimen of steroid replacement of oral estradiol valerate and progesterone (P) by intravaginal suppository was developed for women with premature ovarian failure or ovarian agenesis. The regimen, based on a 28-day cycle, resulted in peripheral plasma concentrations of estradiol and P within the normal range of the menstrual cycle and endometrial differentiation consistent with the normal secretory phase. Pregnancy has now been successfully established in four patients following this regimen of steroid treatment and transfer of donated embryos. Plasma concentrations of LH were within the normal range by the end of the first cycle of treatment with exogenous steroids. However, plasma FSH remained above the normal range, even during the third treatment cycle, consistent with the necessity of a gonadal feedback factor (inhibin?) other than estradiol and P for maintaining FSH in the normal range. Although 7/8 patients had a surge of LH at midcycle, only 3/8 patients had concomitant FSH surges, supporting a role for progesterone in facilitating the midcycle FSH surge.

Conservative treatment of urinary incontinence in women with special reference to the use of oestrogens

Urinary incontinence was treated conservatively in 100 patients. The follow-up period was 12–24 mth. For post-menopausal women, the oestrogen therapy consisted of oral oestradiol valerate or vaginal oestrone sulphate combined with emepronium bromide. In post-menopausal patients the best results were noted when incontinence had begun at the menopause and when the duration of the complaint was not more than 3 yr. For pre-menopausal patients, the treatment given was generally emepronium bromide. During the follow-up period 15 of the patients, 11 of whom were post-menopausal, became symptomless and 77 improved; that is, the incontinence was only slight and occasional. The treatment was without any effect in 8 of the patients. Oestrogen therapy was successful in most post-menopausal women. In these patients, the best results were obtained when the duration of the incontinence was not more than 3 yr.

Serum oestrone, oestradiol and oestriol concentrations during oral oestradiol valerate and oestriol succinate therapy in ovariectomized women

Serum oestrone, oestradiol and oestriol concentrations were investigated during oral treatment with oestradiol valerate and oestriol succinate in ovariectomized women. The dosages used were 1 mg oestradiol valerate in the morning and 2 mg oestriol succinate in the evening of the first day and 2 mg oestradiol valerate in the morning of the second day of treatment. The other group of patients received the same therapy in reverse order. The variations in the serum oestrone and oestradiol concentrations with a daily dose of 1 or 2 mg of oestradiol valerate were considerable. 2 mg oestriol succinate caused a fairly small elevation of serum oestriol concentration. In both treatment groups the quotient E 3/(E 2 + E 1) was similar to that found at the 6–7th day and in the middle of the normal menstrual cycle, the quotient E 1/(E 2 + E 3) was somewhat higher than during normal cycle.

Quantitative aspects of oestrogen metabolism in relation to the menopause and post-menopausal hormone replacement therapy

SummaryQuantitation of the endocrine effects of primary ovarian failure and of pure natural oestrogen therapy was studied by determining Cortisol, androstenedlone, testosterone, oestrone, oestradiol and gonadotropin concentrations on plasma samples obtained every 20 or 30 minutes for 24 hours. In post-menopausal women, only oestradiol levels were low when compared to mid-follicular phase levels in pre-menopausal women. Oestradiol, and particularly oestrone levels, showed marked independent fluctuations which were not temporally related to fluctuations in the androstenedlone levels, even after its acute suppression by dexamethasone, and then its stimulation by synthetic ACTH. After oral piperazine oestrone sulphate or oestradiol valerate, the oestrone concentrations rose to abnormally high levels, whereas oestradiol levels only showed a small rise which was insufficient to replace the circulating oestradiol deficiency which results from primary ovarian failure. Because of marked fluctuations in oestrone an...